This invention is directed to ARL, a compound which exhibits acute vasodilator as well as antihypertensive properties. In the prior art, compositions were extracted from rabbit medulla and have been shown at high doses to provide antihypertensive activity and vasodepression activity (see Muirhead, E. E. et al, J. Lab. & Clin. Med. 56:167, 1960 and the other Muirhead et al references in Proceedings of the Seminar on Hypertension, Supplement to Annals of Academy of Medicine, The Academy of Singapore, V. 5, No. 3, July 1976, pp 36-44.
However, such prior compounds have been low in potency and in many cases the results were not reproducible, i.e., activity seemed to disappear on a batch by batch basis.
In the present invention it has now been possible consistently to reproduce antihypertensive activity and for the first time produce acute vasodilator activity, i.e., a reduction in blood pressure of 30-50% in less than one minute with extremely small doses, e.g., with a single dose of 5 to 20.times.10.sup.-6 grams per kg (I.V.) of the isolated ARL compound as produced herein when administered to a rat. In addition, with this invention lowering of blood pressure is accomplished for periods of from 2 to 4 days in duration with four doses of 10-25.times.10.sup.-6 grams of the ARL compound administered (I.V.) to the rat for two successive days.
Thus, the ARL compound of this invention is useful in mammals as vasodilators in conditions where afterload on the heart should be decreased (as an after load reducer), especially heart failure due to intrinsic disease of the heart muscle, e.g., cardiomyopathy, without producing substantial tachycardia (a side effect encountered with many acute vasodilators) or other dysfunction of the heart. The ARL compound of this invention would also be useful in treating cardiogenic shock, mitral regurgitation, acute myocardial infarction and protracted congestive heart failure at the doses above.
The ARL compound of this invention is also useful in mammals to treat high blood pressure (hypertension) by lowering arterial pressure. The ARL compound of the invention when used as antihypertensives would be administered a few times a day initially and then reduced maintenance doses would be administered to the mammal.
The normal dose of ARL compound for the treatment of mammals such as rats, dogs, cats, humans of the aforementioned conditions would be 5 to 30 micrograms/kg body weight with a single dose of about 15-20 micrograms being given to achieve acute vasodilatation or treat cardiogenic shock. For use of the compound as an antihypertensive a dosage preferably of 30 to 50 micrograms/kg would be given twice daily for two days and thereafter, a maintenance dose of 20 micrograms/kg of body weight would be administered daily. Thus, a unit dose of the ARL compound in humans would be 2 mg to 5 mg.
The ARL compound is preferably administered parenterally or less preferably, as a suppository in a pharmaceutically acceptable carrier. Most preferably, the ARL compound is injected in a suitable pharmaceutically acceptable vehicle in solution into a vein (I.V.); however, it may be injected into an artery, into muscle, i.e., intramuscularly, or subcutaneously, or may be infused I.V. in saline or Ringer's solution. The administration of ARL compound of this invention will, of course, be administered in accordance with the physician's instructions and the actual dose used will be based on the observations and discretion of the physician. The mode of administration of the ARL compound will be selected by the physician in attendance; however, best results to date have been with the parenteral I.V. injections using a single dose bolus or a multi-dose vial from which single doses of the ARL compound in solution in a pharmaceutically acceptable carrier are withdrawn. The compositions for injection must, of course, be sterile and desirably isotonic with the blood of the mammal into which they are being administered.
A suitable diluent is 2% saline and, in addition, solubilizing additives such as albumin or lecithin may be added. Advantageously, the ARL compound is suspended dissolved in a sterile diluent under aseptic conditions. Sterilization of the injection compositions may be effected by conventional techniques. In addition, injectable preparations may be made by adding sterile water to a tube containing the compound as a solid to form a unit dose or a multi-dose.
The ARL compound of this invention may be prepared from isolated rabbit medulla as follows: The rabbit medulla is removed from a slaughtered rabbit, is homogenized and incubated, e.g., from 10 minutes to 2 hrs. at about 25.degree. to 40.degree. C. and most preferably 37.degree. C., approximately the body temperature of the rabbit, for a time sufficient to permit the medulla to produce a substance which, after lipid extraction, produces a yellow oil. Thereafter, the yellow oil is reduced, acetylated, passed through a silicic acid column and then purified through twice using thin layer chromatography to provide the ARL compound.
It has been found that without the incubation step amounts of material obtained from the medulla are not sufficient or cannot be detected to produce the desired end product, i.e., the ARL compound since the material which is needed to produce the ARL compound appears not to be available if conditions are not acceptable within the medulla after the medulla is removed from the body and not held under proper temperature and conditions for a sufficient time after removal from the body of the animal (rabbit).